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MicroRNA-146a and microRNA-146b regulate human dendritic cell apoptosis and cytokine production by targeting TRAF6 and IRAK1 proteins.

ABSTRACT: We have previously reported 27 differentially expressed microRNAs (miRNAs) during human monocyte differentiation into immature dendritic cells (imDCs) and mature DCs (mDCs). However, their roles in DC differentiation and function remain largely elusive. Here, we report that microRNA (miR)-146a and miR-146b modulate DC apoptosis and cytokine production. Expression of miR-146a and miR-146b was significantly increased upon monocyte differentiation into imDCs and mDCs. Silencing of miR-146a and/or miR-146b in imDCs and mDCs significantly prevented DC apoptosis, whereas overexpressing miR-146a and/or miR-146b increased DC apoptosis. miR-146a and miR-146b expression in imDCs and mDCs was inversely correlated with TRAF6 and IRAK1 expression. Furthermore, siRNA silencing of TRAF6 and/or IRAK1 in imDCs and mDCs enhanced DC apoptosis. By contrast, lentivirus overexpression of TRAF6 and/or IRAK1 promoted DC survival. Moreover, silencing of miR-146a and miR-146b expression had little effect on DC maturation but enhanced IL-12p70, IL-6, and TNF-? production as well as IFN-? production by IL-12p70-mediated activation of natural killer cells, whereas miR-146a and miR-146b overexpression in mDCs reduced cytokine production. Silencing of miR-146a and miR-146b in DCs also down-regulated NF-?B inhibitor I?B? and increased Bcl-2 expression. Our results identify a new negative feedback mechanism involving the miR-146a/b-TRAF6/IRAK1-NF-?B axis in promoting DC apoptosis.

SUBMITTER: Park H

PROVIDER: S-EPMC4317016 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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MicroRNA-146a and microRNA-146b regulate human dendritic cell apoptosis and cytokine production by targeting TRAF6 and IRAK1 proteins.

Park Haein H Huang Xin X Lu Changming C Cairo Mitchell S MS Zhou Xianzheng X

The Journal of biological chemistry 20141211 5

We have previously reported 27 differentially expressed microRNAs (miRNAs) during human monocyte differentiation into immature dendritic cells (imDCs) and mature DCs (mDCs). However, their roles in DC differentiation and function remain largely elusive. Here, we report that microRNA (miR)-146a and miR-146b modulate DC apoptosis and cytokine production. Expression of miR-146a and miR-146b was significantly increased upon monocyte differentiation into imDCs and mDCs. Silencing of miR-146a and/or m ...[more]

PMID: 25505246

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Project description:BACKGROUND:microRNA-146a-5p (miRNA-146a-5p) is a key molecule in the negative regulation pathway of TLRs and IL-1 receptor (TIR) signaling. Our recent study demonstrated that MyD88-dependent signaling pathway of TIR in the dorsal root ganglion (DRG) and spinal dorsal horn (SDH) plays a role in peripheral nerve injury-induced neuropathic pain. However, it was not clear whether and how miRNA-146a-5p regulates the TIR pathway of DRG and SDH in the development of neuropathic pain. METHODS:The sciatic nerve chronic constriction injury (CCI) model of rat was used to induce chronic neuropathic pain. The levels and cellular distribution of miRNA-146a-5p were detected with quantitative real-time PCR (qPCR) and fluorescent in situ hybridization (FISH). The RNA level, protein level, and cellular distribution of IRAK1 and TRAF6 that is targeted by miRNA-146a-5p were detected with qPCR, western blot, and immunofluorescent. The pain-related behavioral effect of miRNA-146a-5p was accessed after intrathecal administration. Mechanical stimuli and radiant heat were used to evaluate mechanical allodynia and thermal hyperalgesia. RESULTS:We found that the level of miRNA-146a-5p significantly increased in L4-L6 DRGs and SDH after CCI surgery; meanwhile, the protein level of IRAK1 and TRAF6 in DRGs was significantly increased after CCI. Intrathecal injection of miR146a-5p agomir or miRNA-146a-5p antagomir regulates miRNA-146a-5p level of L4-L6 DRGs and SDH. We found that intrathecal injection of miR146a-5p agomir can alleviate mechanical and thermal hyperalgesia in CCI rats and reverse the upregulation of IRAK1 and TRAF6 of L4-L6 DRGs and SDH induced by CCI. We furthermore found that intrathecal injection of miRNA-146a-5p antagomir can exacerbate the mechanical and thermal pain-related behavior of CCI rats and meanwhile increase IRAK1 and TRAF6 of L4-L6 DRGs and SDH expression even further. CONCLUSIONS:miRNA-146a-5p of DRG and SDH can modulate the development of CCI-induced neuropathic pain through inhibition of IRAK1 and TRAF6 in the TIR signaling pathway. Hence, miRNA-146a-5p may serve as a potential therapeutic target for neuropathic pain.

Project description:BackgroundSarcopenia during aging is closely linked to sterile, low-grade, chronic inflammation. However, considering the increasingly aging global population, the effectiveness of existing treatments for sarcopenia is not exact, and acupuncture, as an effective anti-inflammatory therapy, has the potential to treat it.MethodsFifty Sprague-Dawley rats were randomly allocated into five groups, including Control group, D-galactose (D-gal) group, D-gal + acupuncture (DA) group, D-gal + non-acupoint (DN) group and D-gal amino acid mixture (DAA) group. An aging rat was model constructed using D-gal for 12 weeks. Rats in the control group received 0.9% physiological saline daily. Treatment groups were acupunctured or given amino acid mixture interventions daily, and lasted for last 4 consecutive weeks. The effects of acupuncture were evaluated by the hematoxylin and eosin staining (H&E), transmission electron microscopic (TEM) examination and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays. The anti-inflammatory mechanism of acupuncture was studied by using the expressions of microRNA-146a (miR-146a) mediated nuclear factor-kappa B (NF-κB) signaling pathway-related proteins were detected by immunofluorescence, western blotting, quantitative real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA).ResultsRats injected by D-galactose (D-gal) revealed apparent skeletal muscle atrophy with significantly reduced cross-sectional area and fiber diameter. In contrast, acupuncture treatment alleviated these hallmarks of skeletal muscle atrophy and mitigated the mitochondrial aberrations and skeletal muscle apoptosis in D-gal rats. In addition, acupuncture also downgraded the overexpression of inflammatory factors in skeletal muscle, influenced miR-146a and the target genes level, and inhibited NF-κB nuclear translation in D-gal rats.ConclusionsAcupuncture may ameliorate skeletal muscle atrophy, and its effects may be associated with the control of mitochondrial function regulation and the suppression of inflammation.

Dataset Information

MicroRNA-146a and microRNA-146b regulate human dendritic cell apoptosis and cytokine production by targeting TRAF6 and IRAK1 proteins.

Publications

MicroRNA-146a and microRNA-146b regulate human dendritic cell apoptosis and cytokine production by targeting TRAF6 and IRAK1 proteins.

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